Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI

NCT01569568 | Completed Results DMC

• 1 other identifier: UCRDC 5107
• Study Type: observational
• Target: 49
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this study is to use various types of MRI and cognitive testing to evaluate changes in the brain and cognitive function that occur in subjects with ornithine transcarbamylase deficiency (OTCD) relative to healthy individuals

Conditions

Ornithine Transcarbamylase Deficiency

Keywords

Neuroimaging; MRI; Urea cycle; hyperammonemia; cognitive function; ornithine transcarbamylase deficiency

Outcome Measures

Primary Outcomes (3)

• Concentration of Glutamine and Myoinositol

  Concentration based on area under curve on 1H Magnetic Resonance Spectroscopy(MRS) and quantitated by LCModel (a method that allows automatic quantitation of spectroscopy data). A metabolite's tissue concentration is related to the integrated amplitude, the area under the curve of the MRS signal, it produces. While MRS signals are usually acquired in the time domain as free induction decays or echoes, they are usually viewed and analyzed in the frequency domain. The frequency domain representation is derived from the acquired time domain data by the Fourier Transform. The protocol we use selects 257 averages. The machine summates the data at each time point to generate one value for the area under the curve. Therefore, we don't have the measurement at each time point. Furthermore, we measured voxels in two different brain areas containing different kinds of brain matter: one voxel was located in posterior cingulate gray matter (PCGM) and the other in parietal white matter (PWM).

  Baseline

• Functional Connectivity of Assessed by Resting-state fMRI

  Investigation of differences in functional connectivity of OTCD patients compared to healthy controls, particularly in the default-mode network (DMN) and the set-maintenance network (SMN). Participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, identified the nodes that comprised each network in each group, and assessed internodal connectivity. For each subject, this analysis generated a correlation value, which reflected the strength of functional connectivity between each ROI pair.The correlation r-values were normalized using Fisher's r-to-Z-transform, generating z-scores. The DMN was composed of 1) anterior cingulate/medial prefrontal cortex (ACC/mPFC), 2) posterior cingulate cortex (PCC), and 3) bilateral inferior parietal lobule (IPL). The SMN was composed of 1)ACC, 2) bilateral superior frontal gyrus (SFG), and 3) bilateral anterior insula/frontal operculum (aI/fO).

  Baseline

• Fractional Anisotropy Assessed Using DTI

  Fractional Anisotropy (FA) is a measure of the diffusion asymmetry within a voxel as defined by its eigenvalues. In our study, FA is being used as a measure of white matter integrity, because FA is very sensitive to small microstructural changes.Fractional anisotropy (FA) is a scalar value between zero and one (0-1) that describe anisotropy of a diffusion process. A value of zero means that diffusion is isotropic, i.e. it is unrestricted (or equally restricted) in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all other directions.

  Baseline

Secondary Outcomes (1)

• Neuropsychological Assessment

  Baseline

Study Arms (2)

Subjects with OTCD

males and females ages 7-60 years with OTCD who are able to undergo MRI and cognitive testing MRI scanning 1H MRS, DTI, FMRI Cognitive testing Neuropsychological testing

Other: MRI scanning; Behavioral: Cognitive testing

Healthy controls

males and females ages 7-60 years who are healthy controls who are able to undergo MRI and cognitive testing MRI scanning 1H MRS, DTI, FMRI Cognitive testing Neuropsychological testing

Other: MRI scanning; Behavioral: Cognitive testing

Interventions

MRI scanning OTHER

1H MRS, DTI, FMRI

Also known as: MRI

Healthy controls; Subjects with OTCD

Cognitive testing BEHAVIORAL

Behavioral testing

Healthy controls; Subjects with OTCD

Eligibility Criteria

• Age: 7 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Probability Sample

Study Population

Males and females, ages 7-60 years with ornithine transcarbamylase deficiency Males and females, ages 7-60 years who are healthy controls without ornithine transcarbamylase deficiency

You may qualify if:

• Patients with OTCD;
• Age range: 7-60 years
• Able to undergo neuroimaging safely (i.e. without presence of ferromagnetic devices)
• Subject has a documented full scale IQ \> 70
• Healthy males and females without metabolic disease aged 7-60 years
• Subject has a documented full scale IQ \> 70

You may not qualify if:

• Mental retardation (i.e., Full Scale IQ\< 70)
• Age range \<7 or \>60 years
• Presence of ferromagnetic device(s) that preclude safe imaging
• Pregnant female
• Subjects with a documented history of an intellectual deficit (i.e., Full Scale IQ\< 70)
• Age range \<7 or \>60 years
• Presence of ferromagnetic device(s) that preclude safe imaging
• Pregnant female

Sponsors & Collaborators

• Andrea Gropman: lead
• Children's National Research Institute: collaborator

Related Publications (7)

• Gropman AL, Shattuck K, Prust MJ, Seltzer RR, Breeden AL, Hailu A, Rigas A, Hussain R, VanMeter J. Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: an fMRI study. Hum Brain Mapp. 2013 Apr;34(4):753-61. doi: 10.1002/hbm.21470. Epub 2011 Nov 23.

  PMID: 22110002 BACKGROUND

• Prust MJ, Gropman AL, Hauser N. New frontiers in neuroimaging applications to inborn errors of metabolism. Mol Genet Metab. 2011 Nov;104(3):195-205. doi: 10.1016/j.ymgme.2011.06.020. Epub 2011 Jun 30.

  PMID: 21778100 BACKGROUND

• Gropman AL, Gertz B, Shattuck K, Kahn IL, Seltzer R, Krivitsky L, Van Meter J. Diffusion tensor imaging detects areas of abnormal white matter microstructure in patients with partial ornithine transcarbamylase deficiency. AJNR Am J Neuroradiol. 2010 Oct;31(9):1719-23. doi: 10.3174/ajnr.A2122. Epub 2010 May 20.

  PMID: 20488904 BACKGROUND

• Gropman A. Brain imaging in urea cycle disorders. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S20-30. doi: 10.1016/j.ymgme.2010.01.017. Epub 2010 Feb 13.

  PMID: 20207564 BACKGROUND

• Oldham MS, VanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts. Pediatr Neurol. 2010 Jan;42(1):49-52. doi: 10.1016/j.pediatrneurol.2009.07.017.

  PMID: 20004862 BACKGROUND

• Gropman AL, Sailasuta N, Harris KC, Abulseoud O, Ross BD. Ornithine transcarbamylase deficiency with persistent abnormality in cerebral glutamate metabolism in adults. Radiology. 2009 Sep;252(3):833-41. doi: 10.1148/radiol.2523081878. Epub 2009 Jun 30.

  PMID: 19567648 BACKGROUND

• Gropman AL, Fricke ST, Seltzer RR, Hailu A, Adeyemo A, Sawyer A, van Meter J, Gaillard WD, McCarter R, Tuchman M, Batshaw M; Urea Cycle Disorders Consortium. 1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase deficiency. Mol Genet Metab. 2008 Sep-Oct;95(1-2):21-30. doi: 10.1016/j.ymgme.2008.06.003. Epub 2008 Jul 26.

  PMID: 18662894 BACKGROUND

Related Links

• Family support group
• Urea Cycle rare disease consortium

MeSH Terms

Conditions

Ornithine Carbamoyltransferase Deficiency Disease; Hyperammonemia

Interventions

Neuropsychological Tests

Condition Hierarchy (Ancestors)

Urea Cycle Disorders, Inborn; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Psychological Tests; Behavioral Disciplines and Activities

Results Point of Contact

• Title: Dr. Andrea Gropman
• Organization: Children's National Medical Center

agropman@childrensnational.org

202-476-2120

Study Officials

• Andrea L Gropman, M.D.

  Children's National Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: March 30, 2012
• First Posted: April 3, 2012
• Study Start: September 1, 2010
• Primary Completion: August 1, 2014
• Study Completion: August 1, 2014
• Last Updated: March 8, 2024
• Results First Posted: April 14, 2017

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share